- Email: [email protected]
Combining complementary lipid-lowering agents ezetimibe and lovastatin is superior to either drug alone
TREATMENT
Combining complementary lipid-lowering agents ezetimibe and lovastatin is superior to either drug alone Abstracted from: Kerzner B, Corbelli J, Sharp S et al. Efficacy and safety of ezetimibe co-administered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003; 91: 418 ^ 424.
BACKGROUND Combination therapy for hypercholesterolemia with lipid-lowering agents that have complementary modes of action may result in more patients achieving target cholesterol goals. Ezetimibe inhibits the intestinal absorption of cholesterol. Combining ezetimibe with drugs that reduce cholesterol synthesis (such as statins) may be an e¡ective way of improving cholesterol control in people who are partially resistant to statins alone. OBJECTIVE To assess the e⁄cacy and safety of the combination of ezetimibe plus lovastatin in primary hypercholesterolemia. SETTING Sixty-two centers in the US. METHOD Multicenter, randomized, double-blind, study. PARTICIPANTS Five hundred and forty-eight patients with LDL cholesterol 4145 mg/dL (3.75 mmol/ L) and o250 mg/dL (6.47 mmol/L) and triglycerides o350 mg/dL (3.99 mmol/L). INTERVENTION After dietary stabilization, a 2to 12-week washout period, and a 4-week single-blind placebo lead-in period, patients were randomized to one of the following, administered daily for 12 weeks: ezetimibe 10 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo. MAIN OUTCOMES Change in direct LDL cholesterol from baseline to endpoint for pooled ezetimibe plus lovastatin data versus pooled data for lovastatin alone, change in calculated LDL cholesterol, HDL
1361-2611/03/$ - see front matter & 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1361-2611(03)00072-1
cholesterol, total cholesterol, triglycerides, compliance (see Table 1). MAIN RESULTS Ezetimibe 10 mg plus lovastatin, when compared with placebo, reduced mean LDL cholesterol by 33% to 45%, median triglyceride by 19% to 27%, and increased mean HDL cholesterol by 8% to 9%, depending on the statin dose. Ezetimibe (10 mg) plus lovastatin (all doses) signi¢cantly improved LDL cholesterol, HDL cholesterol, and triglycerides, compared with lovastatin alone (all doses pooled) or ezetimibe 10 mg alone ( po0.01 for all variables). Ezetimibe 10 mg plus lovastatin (all doses pooled) resulted in an incremental 14% fall in LDL cholesterol, 5% rise in HDL cholesterol, and 10% fall in triglycerides, compared with pooled lovastatin alone. Combining ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable e⁄cacy to high-dose lovastatin (40 mg) across the lipid pro¢le (LDL cholesterol, HDL cholesterol, and triglycerides). Ezetimibe plus lovastatin was well tolerated, with a safety pro¢le similar to both lovastatin alone and placebo. AUTHORS’ CONCLUSIONS Combining ezetimibe and lovastatin improves lipid pro¢le compared with each agent alone. This combination is well tolerated and may improve lipid management in people with hypercholesterolemia. Sources offunding: Funding notspecified. Correspondence to: L Melani, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Email: [email protected]
Abstract provided by Bazian Ltd, London.
Evidence-based Cardiovascular Medicine (2003) 7,147^149
147
Table 1 Changes in lipid parameters at 12 weeks Placebo (n = 60 to 64, depending on the outcome)
Ezetimibe 10 mg (n = 67 to 72, depending on the outcome)
All lovastatin (all doses pooled) (n = 202 to 220, depending on the outcome)
Ezetimibe 10 mg + all lovastatin (n = 181 to 192, depending on the outcome)
p value ezetimibe 10 mg + all lovastatin v lovastatin (pooled)
p value ezetimibe 10 mg + all lovastatin v ezetimibe
Change in direct LDL cholesterol from baseline (% [SE])
0 [2]
19 [2]
25 [1]
39 [1]
o0.01
o0.01
Change in calculated LDL cholesterol from baseline (% [SE])
0 [2]
19 [2]
25 [1]
40 [1]
o0.01
o0.01
Change in total cholesterol from baseline (% [SE])
1 [1]
13 [1]
18 [1]
29 [1]
o0.01
o0.01
Change in triglycerides from baseline (% [SE])
4 [3]
3 [3]
11 [2]
22 [2]
o0.01
o0.01
Change in HDL cholesterol from baseline (% [SE])
0 [1]
3 [1]
4 [1]
9 [1]
o0.01
o0.01
Change in direct LDL cholesterol:HDL cholesterol from baseline (% [SE])
1 [2]
21 [2]
27 [1]
43 [1]
o0.01
o0.01
Changes expressed as least-squares mean and SE from analysis of variance on the last observation carried forward in the intent-to-treat population.
148
Evidence-based Cardiovascular Medicine (2003) 7,147^149
Commentary 1 Ezetimibe is the first novel lipid-lowering drug approved by the FDA in over15 years. Ezetimibe is active in the intestines, inhibiting the absorption of biliary and dietary cholesterol, and results in a reduction in LDL of about19%. In this study, ezetimibe, in combination with lovastatin 10, 20 and 40 mg, resulted in additive effects on LDL. Adding ezetimibe to lovastatin is comparable to tripling the dose of the drug (lovastatin10 mg plus10 mg of ezetimibe lowered LDL by 34%, while lovastatin 40 mg lowered LDL by 31%). Effects on HDL and triglycerides were additive as well.The combination of both drugs was also safe and well tolerated. This study continues to emphasize the advantages of adding two complimentary drugs together to maximize both safety and efficacy of lipid-lowering therapy. The approval of ezetimibe comes at a time when physicians are becoming more aggressive in achieving the NCEP ATP III goals. At the same time, the withdrawal of cerivastatin due to an increased rate of rhabdomyolysis has raised concerns about statin safety. In addition, there are a number of patients (perhaps up to 5%) who develop myalgias with statins. Ezetimibe is, therefore, a timely alternative for hyperlipidemic patients who are statin intolerant. It is also an adjunctive option to lower LDL when the maximally tolerated statin dose is insufficient to achieve the ATP III goals. Physicians are reluctant to titrate up statin monotherapy, especially above 40 mg. This reluctance is well founded, since titration from 40 mg to 80 mg results in only a 5%^ 6% additional reduction in LDL, but a 3- to 4 -fold increase in liver function abnormalities (0.5% to 2.5%), and a 10 -fold increase in myopathy (0.05% to 0.5%). The challenge for physicians is to achieve further lipid modification without increasing the risk of drug-induced complications. Although statins are very safe, myopathy has occurred with all statins if the dose is escalated beyond a safe range. Ezetimibe is in many ways comparable to hydrochlorothiazide, which enhances the effects of most anti-hypertensive drugs and, therefore, allows better blood pressure control at lower doses of
Commentary 2 The development of the statins represented a major advancement in the management of patients with elevated low-density lipoprotein cholesterol (LDL-C). There remain, however, many patients whose LDL-C levels are not optimally controlled on statins, and some patients who cannot tolerate statins. This has fuelled the ongoing search for novel lipid-modifying drugs. Ezetimibe is a novel drug that inhibits absorption of dietary and biliary cholesterol without affecting absorption of triglycerides or fat-soluble vitamins. The multicenter, randomized, double-blind, placebo-controlled clinical study by Kerzner et al. assessed the efficacy and safety of ezetimibe plus lovastatin in people with primary hypercholesterolemia. Ezetimibe plus lovastatin significantly improved concentrations of LDL-C, HDL-C and triglycerides compared with lovastatin alone. Notably, the co-administration of ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable efficacy to high-dose
drug when used in combination. With the advent of ezetimibe, lipid-lowering therapy is also shifting to the use of combinations to maximize achievement of the NCEPATP III goals for both LDL and non-HDL, while avoiding potentially significant adverse drug reactions. Michael H. Davidson MD Director of Preventive Cardiology Rush-Presbyterian-St. Luke’s Medical Center Chicago, USA
Literature cited 1. Davidson, MH. Combination therapy for dyslipidemia: safety and regulatory considerations. Am J Cardiol 2002; 90(suppl): 50K^ 60K. 2. Ballantyne C, Houri J, Notarbartolo A, Melani L, Lipka L, LeBeaut A, Suresh R, Sun S, Veltri E, for the Ezetimibe Study Group. Ezetimibe co-administered with atorvastatin in 628 patients with primary hypercholesterolemia (abstract). J Am Coll Cardiol 2002; 39(suppl A): 227A. 3. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S,Veltri EP. Ezetimibe co-administered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40: 2125^2134. 4. Melani L, Mills R, Hassman D, Lipetz R, Lipka L, LeBeaut A, Suresh R, Mukhopadhyay P, Veltri V, for the Ezetimibe Study Group. Ezetimibe co-administered with pravastatin in 538 patients with primary hypercholesterolemia (abstract). J Am Coll Cardiol 2002; 39(suppl B): 139B. 5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA1993; 269: 3015^3023.
lovastatin (40 mg). Although the rate of transaminase elevation in the current study was less than1%, there are a number of studies that have reported higher rates of hepatic transaminase elevation with ezetimibe plus statins (0.7% for statin alone v 2.1% for ezetimibe plus statin). In contrast, there does not appear to be any increase in muscle-related adverse effects when statins are combined with ezetimibe. Based on the large evidence base supporting the use of statins, initiation and dose escalation of statins should remain the preferred method of attaining LDL-C goal. Ezetimibe will be a very useful drug in the management of patients who cannot tolerate statins or statin dose escalation, or whose LDL-C remains uncontrolled on maximum statin therapy. Dr Carl Vaughan Assistant Professor of Clinical Medicine Weill Medical College of Cornell University and on the staff of New York-Presbyterian Hospital
Evidence-based Cardiovascular Medicine (2003) 7,147^149
149
Combining complementary lipid-lowering agents ezetimibe and lovastatin is superior to either drug alone Abstracted from: Kerzner B, Corbelli J, Sharp S et al. Efficacy and safety of ezetimibe co-administered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003; 91: 418 ^ 424.
BACKGROUND Combination therapy for hypercholesterolemia with lipid-lowering agents that have complementary modes of action may result in more patients achieving target cholesterol goals. Ezetimibe inhibits the intestinal absorption of cholesterol. Combining ezetimibe with drugs that reduce cholesterol synthesis (such as statins) may be an e¡ective way of improving cholesterol control in people who are partially resistant to statins alone. OBJECTIVE To assess the e⁄cacy and safety of the combination of ezetimibe plus lovastatin in primary hypercholesterolemia. SETTING Sixty-two centers in the US. METHOD Multicenter, randomized, double-blind, study. PARTICIPANTS Five hundred and forty-eight patients with LDL cholesterol 4145 mg/dL (3.75 mmol/ L) and o250 mg/dL (6.47 mmol/L) and triglycerides o350 mg/dL (3.99 mmol/L). INTERVENTION After dietary stabilization, a 2to 12-week washout period, and a 4-week single-blind placebo lead-in period, patients were randomized to one of the following, administered daily for 12 weeks: ezetimibe 10 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo. MAIN OUTCOMES Change in direct LDL cholesterol from baseline to endpoint for pooled ezetimibe plus lovastatin data versus pooled data for lovastatin alone, change in calculated LDL cholesterol, HDL
1361-2611/03/$ - see front matter & 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1361-2611(03)00072-1
cholesterol, total cholesterol, triglycerides, compliance (see Table 1). MAIN RESULTS Ezetimibe 10 mg plus lovastatin, when compared with placebo, reduced mean LDL cholesterol by 33% to 45%, median triglyceride by 19% to 27%, and increased mean HDL cholesterol by 8% to 9%, depending on the statin dose. Ezetimibe (10 mg) plus lovastatin (all doses) signi¢cantly improved LDL cholesterol, HDL cholesterol, and triglycerides, compared with lovastatin alone (all doses pooled) or ezetimibe 10 mg alone ( po0.01 for all variables). Ezetimibe 10 mg plus lovastatin (all doses pooled) resulted in an incremental 14% fall in LDL cholesterol, 5% rise in HDL cholesterol, and 10% fall in triglycerides, compared with pooled lovastatin alone. Combining ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable e⁄cacy to high-dose lovastatin (40 mg) across the lipid pro¢le (LDL cholesterol, HDL cholesterol, and triglycerides). Ezetimibe plus lovastatin was well tolerated, with a safety pro¢le similar to both lovastatin alone and placebo. AUTHORS’ CONCLUSIONS Combining ezetimibe and lovastatin improves lipid pro¢le compared with each agent alone. This combination is well tolerated and may improve lipid management in people with hypercholesterolemia. Sources offunding: Funding notspecified. Correspondence to: L Melani, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Email: [email protected]
Abstract provided by Bazian Ltd, London.
Evidence-based Cardiovascular Medicine (2003) 7,147^149
147
Table 1 Changes in lipid parameters at 12 weeks Placebo (n = 60 to 64, depending on the outcome)
Ezetimibe 10 mg (n = 67 to 72, depending on the outcome)
All lovastatin (all doses pooled) (n = 202 to 220, depending on the outcome)
Ezetimibe 10 mg + all lovastatin (n = 181 to 192, depending on the outcome)
p value ezetimibe 10 mg + all lovastatin v lovastatin (pooled)
p value ezetimibe 10 mg + all lovastatin v ezetimibe
Change in direct LDL cholesterol from baseline (% [SE])
0 [2]
19 [2]
25 [1]
39 [1]
o0.01
o0.01
Change in calculated LDL cholesterol from baseline (% [SE])
0 [2]
19 [2]
25 [1]
40 [1]
o0.01
o0.01
Change in total cholesterol from baseline (% [SE])
1 [1]
13 [1]
18 [1]
29 [1]
o0.01
o0.01
Change in triglycerides from baseline (% [SE])
4 [3]
3 [3]
11 [2]
22 [2]
o0.01
o0.01
Change in HDL cholesterol from baseline (% [SE])
0 [1]
3 [1]
4 [1]
9 [1]
o0.01
o0.01
Change in direct LDL cholesterol:HDL cholesterol from baseline (% [SE])
1 [2]
21 [2]
27 [1]
43 [1]
o0.01
o0.01
Changes expressed as least-squares mean and SE from analysis of variance on the last observation carried forward in the intent-to-treat population.
148
Evidence-based Cardiovascular Medicine (2003) 7,147^149
Commentary 1 Ezetimibe is the first novel lipid-lowering drug approved by the FDA in over15 years. Ezetimibe is active in the intestines, inhibiting the absorption of biliary and dietary cholesterol, and results in a reduction in LDL of about19%. In this study, ezetimibe, in combination with lovastatin 10, 20 and 40 mg, resulted in additive effects on LDL. Adding ezetimibe to lovastatin is comparable to tripling the dose of the drug (lovastatin10 mg plus10 mg of ezetimibe lowered LDL by 34%, while lovastatin 40 mg lowered LDL by 31%). Effects on HDL and triglycerides were additive as well.The combination of both drugs was also safe and well tolerated. This study continues to emphasize the advantages of adding two complimentary drugs together to maximize both safety and efficacy of lipid-lowering therapy. The approval of ezetimibe comes at a time when physicians are becoming more aggressive in achieving the NCEP ATP III goals. At the same time, the withdrawal of cerivastatin due to an increased rate of rhabdomyolysis has raised concerns about statin safety. In addition, there are a number of patients (perhaps up to 5%) who develop myalgias with statins. Ezetimibe is, therefore, a timely alternative for hyperlipidemic patients who are statin intolerant. It is also an adjunctive option to lower LDL when the maximally tolerated statin dose is insufficient to achieve the ATP III goals. Physicians are reluctant to titrate up statin monotherapy, especially above 40 mg. This reluctance is well founded, since titration from 40 mg to 80 mg results in only a 5%^ 6% additional reduction in LDL, but a 3- to 4 -fold increase in liver function abnormalities (0.5% to 2.5%), and a 10 -fold increase in myopathy (0.05% to 0.5%). The challenge for physicians is to achieve further lipid modification without increasing the risk of drug-induced complications. Although statins are very safe, myopathy has occurred with all statins if the dose is escalated beyond a safe range. Ezetimibe is in many ways comparable to hydrochlorothiazide, which enhances the effects of most anti-hypertensive drugs and, therefore, allows better blood pressure control at lower doses of
Commentary 2 The development of the statins represented a major advancement in the management of patients with elevated low-density lipoprotein cholesterol (LDL-C). There remain, however, many patients whose LDL-C levels are not optimally controlled on statins, and some patients who cannot tolerate statins. This has fuelled the ongoing search for novel lipid-modifying drugs. Ezetimibe is a novel drug that inhibits absorption of dietary and biliary cholesterol without affecting absorption of triglycerides or fat-soluble vitamins. The multicenter, randomized, double-blind, placebo-controlled clinical study by Kerzner et al. assessed the efficacy and safety of ezetimibe plus lovastatin in people with primary hypercholesterolemia. Ezetimibe plus lovastatin significantly improved concentrations of LDL-C, HDL-C and triglycerides compared with lovastatin alone. Notably, the co-administration of ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable efficacy to high-dose
drug when used in combination. With the advent of ezetimibe, lipid-lowering therapy is also shifting to the use of combinations to maximize achievement of the NCEPATP III goals for both LDL and non-HDL, while avoiding potentially significant adverse drug reactions. Michael H. Davidson MD Director of Preventive Cardiology Rush-Presbyterian-St. Luke’s Medical Center Chicago, USA
Literature cited 1. Davidson, MH. Combination therapy for dyslipidemia: safety and regulatory considerations. Am J Cardiol 2002; 90(suppl): 50K^ 60K. 2. Ballantyne C, Houri J, Notarbartolo A, Melani L, Lipka L, LeBeaut A, Suresh R, Sun S, Veltri E, for the Ezetimibe Study Group. Ezetimibe co-administered with atorvastatin in 628 patients with primary hypercholesterolemia (abstract). J Am Coll Cardiol 2002; 39(suppl A): 227A. 3. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S,Veltri EP. Ezetimibe co-administered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40: 2125^2134. 4. Melani L, Mills R, Hassman D, Lipetz R, Lipka L, LeBeaut A, Suresh R, Mukhopadhyay P, Veltri V, for the Ezetimibe Study Group. Ezetimibe co-administered with pravastatin in 538 patients with primary hypercholesterolemia (abstract). J Am Coll Cardiol 2002; 39(suppl B): 139B. 5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA1993; 269: 3015^3023.
lovastatin (40 mg). Although the rate of transaminase elevation in the current study was less than1%, there are a number of studies that have reported higher rates of hepatic transaminase elevation with ezetimibe plus statins (0.7% for statin alone v 2.1% for ezetimibe plus statin). In contrast, there does not appear to be any increase in muscle-related adverse effects when statins are combined with ezetimibe. Based on the large evidence base supporting the use of statins, initiation and dose escalation of statins should remain the preferred method of attaining LDL-C goal. Ezetimibe will be a very useful drug in the management of patients who cannot tolerate statins or statin dose escalation, or whose LDL-C remains uncontrolled on maximum statin therapy. Dr Carl Vaughan Assistant Professor of Clinical Medicine Weill Medical College of Cornell University and on the staff of New York-Presbyterian Hospital
Evidence-based Cardiovascular Medicine (2003) 7,147^149
149